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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2770-2779. Prepublished online as a Blood First Edition Paper on June 27, 2006; DOI 10.1182/blood-2006-04-014712. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2006-04-014712v1 108/8/2770    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mercher, T. Articles by Gilliland, D G Search for Related Content PubMed PubMed Citation Articles by Mercher, T. Articles by Gilliland, D G Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 30, 2006 Accepted June 11, 2006 JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model Thomas Mercher, Gerlinde Wernig, Sandra A Moore, Ross L Levine, Ting-Lei Gu, Stefan Frohling, Dana Cullen, Roberto D Polakiewicz, Olivier A Bernard, Titus J Boggon, Benjamin H Lee, and D G Gilliland* Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA Signalling Technology Inc., Danvers, Massachusetts, USA Institut National de la Sante et de la Recherche Medical (INSERM) E0210, Universite Paris V, France Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA * Corresponding author; email: ggilliland{at}rics.bwh.harvard.edu. Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia associated with a poor prognosis. However, there are relatively few insights into the genetic etiology of AMKL. We developed a screening assay for mutations that cause AMKL, based on the hypothesis that constitutive activation of STAT5 would be a biochemical indicator of mutation in an upstream effector tyrosine kinase. We screened human AMKL cell lines for constitutive STAT5 activation, and then used an approach combining mass spectrometry identification of tyrosine phosphorylated proteins and growth inhibition in the presence of selective small molecule tyrosine kinase inhibitors that would inform DNA sequence analysis of candidate tyrosine kinases. Using this strategy, we identified a new JAK2T875N mutation in the AMKL cell line CHRF-288-11. JAK2T875N is a constitutively activated tyrosine kinase that activates downstream effectors including STAT5 in hematopoietic cells in vitro. In a murine transplant model, JAK2T875N induced a myeloproliferative disease characterized by features of AMKL, including megakaryocytic hyperplasia in the spleen; impaired megakaryocyte polyploidization; and increased reticulin fibrosis of the bone marrow and spleen. These findings provide new insights into pathways and therapeutic targets that contribute to pathogenesis of AMKL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z. Xiang, Y. Zhao, V. Mitaksov, D. H. Fremont, Y. Kasai, A. Molitoris, R. E. Ries, T. L. Miner, M. D. McLellan, J. F. DiPersio, et al. Identification of somatic JAK1 mutations in patients with acute myeloid leukemia Blood, May 1, 2008; 111(9): 4809 - 4812. [Abstract] [Full Text] [PDF] G. Wernig, J. R. Gonneville, B. J. Crowley, M. S. Rodrigues, M. M. Reddy, H. E. Hudon, C. Walz, A. Reiter, K. Podar, Y. Royer, et al. The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes Blood, April 1, 2008; 111(7): 3751 - 3759. [Abstract] [Full Text] [PDF] X. Lu, L. J.-S. Huang, and H. F. Lodish Dimerization by a Cytokine Receptor Is Necessary for Constitutive Activation of JAK2V617F J. Biol. Chem., February 29, 2008; 283(9): 5258 - 5266. [Abstract] [Full Text] [PDF] A. Pardanani, T. L. Lasho, C. Finke, R. A. Mesa, W. J. Hogan, R. P. Ketterling, D. G. Gilliland, and A. Tefferi Extending Jak2V617F and MplW515 Mutation Analysis to Single Hematopoietic Colonies and B and T Lymphocytes Stem Cells, September 1, 2007; 25(9): 2358 - 2362. [Abstract] [Full Text] [PDF] T.-l. Gu, T. Mercher, J. W. Tyner, V. L. Goss, D. K. Walters, M. G. Cornejo, C. Reeves, L. Popova, K. Lee, M. C. Heinrich, et al. A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia Blood, July 1, 2007; 110(1): 323 - 333. [Abstract] [Full Text] [PDF] S. Malinge, R. Ben-Abdelali, C. Settegrana, I. Radford-Weiss, M. Debre, K. Beldjord, E. A. Macintyre, J.-L. Villeval, W. Vainchenker, R. Berger, et al. Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia Blood, March 1, 2007; 109(5): 2202 - 2204. [Abstract] [Full Text] [PDF] R. Skoda The Genetic Basis of Myeloproliferative Disorders Hematology, January 1, 2007; 2007(1): 1 - 10. [Abstract] [Full Text] [PDF]

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